Algorithm-driven DNA nanostructure design for advanced functionality

Algorithm-driven DNA nanostructure design for advanced functionality | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Physical Sciences - Article Algorithm-driven DNA nanostructure design for advanced functionality Nicolas Schabanel, Nicolas Levy, Julie Finkel, Allan Mills, Gerrit Wilkens, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7623218/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Form and function are intimately linked—a guiding principle across both biology and engineering. While evolution and human ingenuity have shaped this landscape through function-driven form selection, AI-driven generative design expands it beyond natural and intuitive geometries, enabling the exploration of structure-driven functionalities that were previously inaccessible. At the nanoscale, however, realizing such non-intuitive architectures remains a key challenge, limiting the development of multifunctional nanostructures across biology, chemistry, and materials science. To address these constraints, we introduce an algorithmic design paradigm that enables DNA helices to follow non-planar 3D trajectories, thereby supporting the structural and functional outcomes required for advanced capabilities. We implemented this paradigm in ENSnano, an open-source software platform that integrates mathematical models to automate structural design in 3D space without the need of human intervention. This framework allows us to rapidly generate DNA nanostructures with key functional features such as curvature, encapsulation, and hierarchical organization—reminiscent of naturally occurring biological architectures. As a key application, we demonstrate an automated pathway from biological to engineered structures by designing and experimentally assembling Vault-like cages directly derived from the emPDB model of the Vault protein, marking a step forward in biomimetic DNA nanostructure design. Biological sciences/Biotechnology/Nanobiotechnology/Nanostructures Physical sciences/Mathematics and computing/Software Physical sciences/Chemistry/Biochemistry/DNA Physical sciences/Nanoscience and technology/DNA nanotechnology/DNA nanostructures Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7623218","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":533311237,"identity":"41afc594-088c-4844-a6ee-06d6875c06ad","order_by":0,"name":"Nicolas Schabanel","email":"data:image/png;base64,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","orcid":"","institution":"CNRS","correspondingAuthor":true,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Schabanel","suffix":""},{"id":533311238,"identity":"141e6f96-aaf1-4621-902b-9360b4946cc4","order_by":1,"name":"Nicolas Levy","email":"","orcid":"","institution":"École Normale Supérieure de Lyon, Laboratoire de l'Informatique du Parallélisme","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"Levy","suffix":""},{"id":533311239,"identity":"2a3cb327-9ad9-4a11-b7a0-6d2e9a154266","order_by":2,"name":"Julie Finkel","email":"","orcid":"https://orcid.org/0009-0002-2535-4262","institution":"Université de Montpellier, CNRS, INSERM, Centre de Biologie Structurale","correspondingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Finkel","suffix":""},{"id":533311240,"identity":"fbb747ad-0ff9-485e-9a67-0ef589ee7ddb","order_by":3,"name":"Allan Mills","email":"","orcid":"","institution":"Université de Montpellier, CNRS, INSERM, Centre de Biologie Structurale","correspondingAuthor":false,"prefix":"","firstName":"Allan","middleName":"","lastName":"Mills","suffix":""},{"id":533311241,"identity":"576fc5f7-1315-4c77-8f45-7c0ed88160b2","order_by":4,"name":"Gerrit Wilkens","email":"","orcid":"","institution":"Université de Montpellier, CNRS, INSERM, Centre de Biologie Structurale","correspondingAuthor":false,"prefix":"","firstName":"Gerrit","middleName":"","lastName":"Wilkens","suffix":""},{"id":533311242,"identity":"802115ad-b0ee-4f17-ae6f-f1905d0e76d7","order_by":5,"name":"Anjelica Kucinic","email":"","orcid":"","institution":"Université de Montpellier, CNRS, INSERM, Centre de Biologie Structurale","correspondingAuthor":false,"prefix":"","firstName":"Anjelica","middleName":"","lastName":"Kucinic","suffix":""},{"id":533311243,"identity":"702c1eab-4eec-4622-a78c-b29b5ef0f951","order_by":6,"name":"Aurelie Ancelin","email":"","orcid":"","institution":"CNRS","correspondingAuthor":false,"prefix":"","firstName":"Aurelie","middleName":"","lastName":"Ancelin","suffix":""},{"id":533311244,"identity":"71e6d6a0-61cd-4531-93ee-bac2ad0b7071","order_by":7,"name":"Pierre Marcus","email":"","orcid":"","institution":"École Normale Supérieure de Lyon, Laboratoire de l'Informatique du Parallélisme","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Marcus","suffix":""},{"id":533311245,"identity":"df6bdde7-e049-400b-8a2e-7ea59a6a4eab","order_by":8,"name":"Octave Hazard","email":"","orcid":"","institution":"École Normale Supérieure de Lyon, Laboratoire de l'Informatique du Parallélisme","correspondingAuthor":false,"prefix":"","firstName":"Octave","middleName":"","lastName":"Hazard","suffix":""},{"id":533311246,"identity":"96fa2af2-f92f-4d70-bbb0-6992b83d165d","order_by":9,"name":"Joris Picot","email":"","orcid":"","institution":"École Normale Supérieure de Lyon, Laboratoire de l'Informatique du Parallélisme","correspondingAuthor":false,"prefix":"","firstName":"Joris","middleName":"","lastName":"Picot","suffix":""},{"id":533311247,"identity":"83a04bc3-5671-4c6e-9ee5-a91cc190f6ce","order_by":10,"name":"Daria Pchelina","email":"","orcid":"","institution":"École Normale Supérieure de Lyon, Laboratoire de l'Informatique du Parallélisme","correspondingAuthor":false,"prefix":"","firstName":"Daria","middleName":"","lastName":"Pchelina","suffix":""},{"id":533311248,"identity":"385be1f3-2807-44e1-8cde-84aca0c8ac71","order_by":11,"name":"Gaëtan Bellot","email":"","orcid":"","institution":"Université de Montpellier, CNRS, INSERM, Centre de Biologie Structurale","correspondingAuthor":false,"prefix":"","firstName":"Gaëtan","middleName":"","lastName":"Bellot","suffix":""}],"badges":[],"createdAt":"2025-09-15 17:50:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7623218/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7623218/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96455741,"identity":"5dff65bf-f8c7-4a1d-b02d-9df3826a8fa2","added_by":"auto","created_at":"2025-11-21 10:04:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":99174697,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ensnanonaturesubmitted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7623218/v1_covered_feec0e04-f253-4a5b-8ad1-c82c2e23571a.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Algorithm-driven DNA nanostructure design for advanced functionality","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7623218/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7623218/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Form and function are intimately linked—a guiding principle across both biology and engineering. While evolution and human ingenuity have shaped this landscape through function-driven form selection, AI-driven generative design expands it beyond natural and intuitive geometries, enabling the exploration of structure-driven functionalities that were previously inaccessible.\r\nAt the nanoscale, however, realizing such non-intuitive architectures remains a key challenge, limiting the development of multifunctional nanostructures across biology, chemistry, and materials science.\r\nTo address these constraints, we introduce an algorithmic design paradigm that enables DNA helices to follow non-planar 3D trajectories, thereby supporting the structural and functional outcomes required for advanced capabilities.\r\nWe implemented this paradigm in ENSnano, an open-source software platform that integrates mathematical models to automate structural design in 3D space without the need of human intervention. \r\nThis framework allows us to rapidly generate DNA nanostructures with key functional features such as curvature, encapsulation, and hierarchical organization—reminiscent of naturally occurring biological architectures.\r\nAs a key application, we demonstrate an automated pathway from biological to engineered structures by designing and experimentally assembling Vault-like cages directly derived from the emPDB model of the Vault protein, marking a step forward in biomimetic DNA nanostructure design.","manuscriptTitle":"Algorithm-driven DNA nanostructure design for advanced functionality","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-21 08:13:45","doi":"10.21203/rs.3.rs-7623218/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-nanotechnology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nnano","sideBox":"Learn more about [Nature Nanotechnology](http://www.nature.com/nnano/)","snPcode":"","submissionUrl":"","title":"Nature Nanotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5dc26147-52fe-4db1-9d23-e66494588600","owner":[],"postedDate":"November 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56696781,"name":"Biological sciences/Biotechnology/Nanobiotechnology/Nanostructures"},{"id":56696782,"name":"Physical sciences/Mathematics and computing/Software"},{"id":56696783,"name":"Physical sciences/Chemistry/Biochemistry/DNA"},{"id":56696784,"name":"Physical sciences/Nanoscience and technology/DNA nanotechnology/DNA nanostructures"}],"tags":[],"updatedAt":"2025-11-21T08:13:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-21 08:13:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7623218","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7623218","identity":"rs-7623218","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}